# Bronchus-Associated Lymphoid Tissue & Lung Infection in Down Syndrome

> **NIH NIH R21** · UNIVERSITY OF COLORADO DENVER · 2020 · $194,375

## Abstract

PROJECT SUMMARY
With an incidence of one in 700-1000 live births worldwide, Down Syndrome (DS), or trisomy of human
chromosome 21 (Hsa21), is the most common chromosomal abnormality. While DS is most often recognized
for intellectual disability, congenital malformations, and dysmorphic features, it is also associated with seriously
increased rates and severity of respiratory tract infection (RTI). Indeed, infectious respiratory disease in those
with DS accounts for 54% of hospital admissions and more deaths than any other medical condition. Children
with DS have a 62-fold higher rate of pneumonia than children without DS. During the influenza A (H1N1)
pandemic in 2009, 23% of hospitalized patients with DS died vs. only 0.1% of those without DS. Collectively,
these data point to an urgent need to understand how the condition of trisomy 21 contributes to RTI and to
identify potential therapeutic targets. Currently, RTI in DS is commonly attributed to congenital abnormalities of
the nasopharynx and upper and lower airways. However, our preliminary data support the novel hypothesis
that lung immune cell dysfunction is a primary driver of increased incidence and severity of RTI in DS. Our data
show that the trisomic Dp16 mouse lung is in a state of interferonpathy and is deficient in bronchus-associated
lymphoid tissue (BALT). BALTs are key controllers of a variety of immune and inflammatory responses to
numerous stimuli, including RTI. These changes in the Dp16 mouse lung closely mimic the dysregulated
cytokine response in the human lung that has long been observed following influenza infection, and is a state
linked to increased susceptibility to lethal bacterial pneumonia. Importantly, Dp16 mice are trisomic for the
Hsa21-encoded interferon receptors and interferon-responsive genes. Based on these data, we propose to test
our hypothesis that the constitutive activation state of interferon signaling in the DS lung reduces BALT
biogenesis thus imparting immune suppression and predisposition to respiratory infection with S. pneumoniae.
This state phenocopies the increased susceptibility to and severity of S. pneumoniae respiratory infection that
is observed in typical individuals after a course of viral infection. The high mortality of RTI combined with poor
response to vaccination is an urgent medical need in DS. Our novel paradigm conceptualizes DS as an
interferonopathic state of heightened susceptibility to RTI due to depressed BALT function that mimics the
state of acute viral infection in the typical population. In direct response to the NIH INCLUDE RFA, our
proposal is a proof of concept study in an animal model of DS with high potential payoff that aims to enable
efficient and effective movement of candidate therapeutics towards clinical trials for Down syndrome and RTI.

## Key facts

- **NIH application ID:** 10018101
- **Project number:** 5R21HL151256-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** MICHAEL E. YEAGER
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $194,375
- **Award type:** 5
- **Project period:** 2019-09-15 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10018101

## Citation

> US National Institutes of Health, RePORTER application 10018101, Bronchus-Associated Lymphoid Tissue & Lung Infection in Down Syndrome (5R21HL151256-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10018101. Licensed CC0.

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